tbuckley/cabot-search huggingface dataset:
Adipose Tissue Dysfunction and Energy Balance Paradigms in People Living With HIV
Authors: Claudia E Ramirez Bustamante, Neeti Agarwal, Aaron R Cox, Sean M Hartig, Jordan E Lake, Ashok Balasubramanyam
Journal: Endocrine Reviews (2023)

Over the past 4 decades, the clinical care of people living with HIV (PLWH) evolved from treatment of acute opportunistic infections to the management of chronic, noncommunicable comorbidities. Concurrently, our understanding of adipose tissue function matured to acknowledge its important endocrine contributions to energy balance. PLWH experience changes in the mass and composition of adipose tissue depots before and after initiating antiretroviral therapy, including regional loss (lipoatrophy), gain (lipohypertrophy), or mixed lipodystrophy. These conditions may coexist with generalized obesity in PLWH and reflect disturbances of energy balance regulation caused by HIV persistence and antiretroviral therapy drugs. Adipocyte hypertrophy characterizes visceral and subcutaneous adipose tissue depot expansion, as well as ectopic lipid deposition that occurs diffusely in the liver, skeletal muscle, and heart. PLWH with excess visceral adipose tissue exhibit adipokine dysregulation coupled with increased insulin resistance, heightening their risk for cardiovascular disease above that of the HIV-negative population. However, conventional therapies are ineffective for the management of cardiometabolic risk in this patient population. Although the knowledge of complex cardiometabolic comorbidities in PLWH continues to expand, significant knowledge gaps remain. Ongoing studies aimed at understanding interorgan communication and energy balance provide insights into metabolic observations in PLWH and reveal potential therapeutic targets. Our review focuses on current knowledge and recent advances in HIV-associated adipose tissue dysfunction, highlights emerging adipokine paradigms, and describes critical mechanistic and clinical insights.
Impact of hypertension prevalence trend on mortality and burdens of dementia and disability in England and Wales to 2060: a simulation modelling study
Authors: Yuntao Chen, Marzieh Araghi, Piotr Bandosz, Martin J Shipley, Sara Ahmadi-Abhari, Sophia Lobanov-Rostovsky, Tishya Venkatraman, Mika Kivimaki, Martin O'Flaherty, Eric J Brunner
Journal: The Lancet Healthy Longevity (2023)

BackgroundPrevious estimates of the impact of public health interventions targeting hypertension usually focus on one health outcome. This study aims to consider the effects of change in future hypertension prevalence on mortality, dementia, and disability simultaneously.MethodsWe modelled three plausible scenarios based on observed trends of hypertension prevalence from 2003 to 2017 in England: observed trends continue (baseline scenario); 2017 prevalence remains unchanged; and 2017 prevalence decreases by 50% by 2060. We used a probabilistic Markov model to integrate calendar trends in incidence of cardiovascular disease, dementia, disability, and mortality to forecast their future occurrence in the population of England and Wales. Assuming the hypertension prevalence trend modifies health transition probabilities, we compared mortality outcomes and the burden of dementia and disability to 2060 for the scenarios.FindingsIf the decline in hypertension prevalence stops, there would be a slight increase in the number of additional deaths to 2060 (22·9 [95% uncertainty interval 19·0–26·6] more deaths per 100 000 population), although the burdens of disability and dementia in absolute terms would change little. Alternatively, if the downward hypertension prevalence trend accelerates (with prevalence falling by 50% between 2017 and 2060), there would be a modest additional reduction in deaths (57·0 [50·4–63·5] fewer deaths per 100 000 population), a small increase in dementia burden (9·0 [5·1–13·2] more cases per 100 000 population), no significant effect on disability burden, and an 8% gain in healthy life expectancy at age 65 years from 2020 to 2060 (5·3 years vs 4·9 years) compared with the baseline scenario.InterpretationThe major future impact of alternative hypertension prevention strategies appears to be on future life expectancy. The salutary effect of lower population blood pressure distribution on incidence of dementia and disability might not offset expansion of the susceptible population due to reduced mortality.FundingBritish Heart Foundation and UK Economic and Social Research Council.
The Number and Size of Individual Kidney Medullary Pyramids is Associated with Clinical Characteristics, Kidney Biopsy Findings, and CKD Outcomes among Kidney Donors
Authors: Adriana V. Gregory, Aleksandar Denic, Amr Moustafa, Praveen G. Dasaraju, Bhavya Poudyal, Joshua J. Augustine, Aidan F. Mullan, Panagiotis Korfiatis, Andrew D. Rule, Timothy L. Kline
Journal: Journal of the American Society of Nephrology (2023)

Significance Statement Segmentation of multiple structures in cross-sectional imaging is time-consuming and impractical to perform manually, especially if the end goal is clinical implementation. In this study, we developed, validated, and demonstrated the capability of a deep learning algorithm to segment individual medullary pyramids in a rapid, accurate, and reproducible manner. The results demonstrate that cortex volume, medullary volume, number of pyramids, and mean pyramid volume is associated with patient clinical characteristics and microstructural findings and provide insights into the mechanisms that may lead to CKD. Background The kidney is a lobulated organ, but little is known regarding the clinical importance of the number and size of individual kidney lobes. Methods After applying a previously validated algorithm to segment the cortex and medulla, a deep-learning algorithm was developed and validated to segment and count individual medullary pyramids on contrast-enhanced computed tomography images of living kidney donors before donation. The association of cortex volume, medullary volume, number of pyramids, and mean pyramid volume with concurrent clinical characteristics (kidney function and CKD risk factors), kidney biopsy morphology (nephron number, glomerular volume, and nephrosclerosis), and short- and long-term GFR &lt;60 or &lt;45 ml/min per 1.73 m 2 was assessed. Results Among 2876 living kidney donors, 1132 had short-term follow-up at a median of 3.8 months and 638 had long-term follow-up at a median of 10.0 years. Larger cortex volume was associated with younger age, male sex, larger body size, higher GFR, albuminuria, more nephrons, larger glomeruli, less nephrosclerosis, and lower risk of low GFR at follow-up. Larger pyramids were associated with older age, female sex, larger body size, higher GFR, more nephrons, larger glomerular volume, more nephrosclerosis, and higher risk of low GFR at follow-up. More pyramids were associated with younger age, male sex, greater height, no hypertension, higher GFR, lower uric acid, more nephrons, less nephrosclerosis, and a lower risk of low GFR at follow-up. Conclusions Cortex volume and medullary pyramid volume and count reflect underlying variation in nephron number and nephron size as well as merging of pyramids because of age-related nephrosclerosis, with loss of detectable cortical columns separating pyramids.
Genotype, oxidase status, and preceding infection or autoinflammation do not affect allogeneic HCT outcomes for CGD
Authors: Jennifer W. Leiding, Danielle E. Arnold, Suhag Parikh, Brent Logan, Rebecca A. Marsh, Linda M. Griffith, Ruizhe Wu, Sharon Kidd, Kanwaldeep Mallhi, Deepak Chellapandian, Stephanie J. Si Lim, Eyal Grunebaum, E. Liana Falcone, Luis Murguia-Favela, Debbi Grossman, Vinod K. Prasad, Jennifer R. Heimall, Fabien Touzot, Lauri M. Burroughs, Jack Bleesing, Neena Kapoor, Jasmeen Dara, Olatundun Williams, Malika Kapadia, Benjamin R. Oshrine, Jeffrey J. Bednarski, Ahmad Rayes, Hey Chong, Geoffrey D. E. Cuvelier, Lisa R. Forbes Satter, Caridad Martinez, Mark T. Vander Lugt, Lolie C. Yu, Shanmuganathan Chandrakasan, Avni Joshi, Susan E. Prockop, Blachy J. Dávila Saldaña, Victor Aquino, Larisa A. Broglie, Christen L. Ebens, Lisa M. Madden, Kenneth DeSantes, Jordan Milner, Hemalatha G. Rangarajan, Ami J. Shah, Alfred P. Gillio, Alan P. Knutsen, Holly K. Miller, Theodore B. Moore, Pamela Graham, Andrea Bauchat, Nancy J. Bunin, Pierre Teira, Aleksandra Petrovic, Sharat Chandra, Hisham Abdel-Azim, Morna J. Dorsey, Olga Birbrayer, Morton J. Cowan, Christopher C. Dvorak, Elie Haddad, Donald B. Kohn, Luigi D. Notarangelo, Sung-Yun Pai, Jennifer M. Puck, Michael A. Pulsipher, Troy R. Torgerson, Harry L. Malech, Elizabeth M. Kang
Journal: Blood (2023)
Loss of endothelial membrane KIT ligand affects systemic KIT ligand levels but not bone marrow hematopoietic stem cells
Authors: Sahoko Matsuoka, Raffaella Facchini, Tiago C. Luis, Joana Carrelha, Petter S. Woll, Takuo Mizukami, Bishan Wu, Hanane Boukarabila, Mario Buono, Ruggiero Norfo, Fumio Arai, Toshio Suda, Adam J. Mead, Claus Nerlov, Sten Eirik W. Jacobsen
Journal: Blood (2023)

A critical regulatory role of hematopoietic stem cell (HSC) vascular niches in the bone marrow has been implicated to occur through endothelial niche cell expression of KIT ligand. However, endothelial-derived KIT ligand is expressed in both a soluble and membrane-bound form and not unique to bone marrow niches, and it is also systemically distributed through the circulatory system. Here, we confirm that upon deletion of both the soluble and membrane-bound forms of endothelial-derived KIT ligand, HSCs are reduced in mouse bone marrow. However, the deletion of endothelial-derived KIT ligand was also accompanied by reduced soluble KIT ligand levels in the blood, precluding any conclusion as to whether the reduction in HSC numbers reflects reduced endothelial expression of KIT ligand within HSC niches, elsewhere in the bone marrow, and/or systemic soluble KIT ligand produced by endothelial cells outside of the bone marrow. Notably, endothelial deletion, specifically of the membrane-bound form of KIT ligand, also reduced systemic levels of soluble KIT ligand, although with no effect on stem cell numbers, implicating an HSC regulatory role primarily of soluble rather than membrane KIT ligand expression in endothelial cells. In support of a role of systemic rather than local niche expression of soluble KIT ligand, HSCs were unaffected in KIT ligand deleted bones implanted into mice with normal systemic levels of soluble KIT ligand. Our findings highlight the need for more specific tools to unravel niche-specific roles of regulatory cues expressed in hematopoietic niche cells in the bone marrow.
CARD11 gain of function upregulates BCL2A1 expression and promotes resistance to targeted therapies combination in B-cell lymphoma
Authors: Salomé Decombis, Celine Bellanger, Yannick Le Bris, Candice Madiot, Jane Jardine, Juliana Carvalho Santos, Delphine Boulet, Christelle Dousset, Audrey Menard, Charlotte Kervoelen, Elise Douillard, Philippe Moreau, Stephane Minvielle, Agnes Moreau-Aubry, Benoit Tessoulin, Gael Roue, Nicolas Bidère, Steven Le Gouill, Catherine Pellat-Deceunynck, David Chiron
Journal: Blood (2023)
Reply to Wu <i>et al</i>.
Authors: Evan L. Brittain, Ryan J. Tedford, Bradley A. Maron
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

"Reply to: Can Pulmonary Arterial Compliance Be a Prognostic Marker for Pulmonary Hypertension?." American Journal of Respiratory and Critical Care Medicine, 0(ja), pp.
Brain tissue mechanics is governed by microscale relations of the tissue constituents
Authors: P. Sáez, C. Borau, N. Antonovaite, K. Franze
Journal: Biomaterials (2023)

Local mechanical tissue properties are a critical regulator of cell function in the central nervous system (CNS) during development and disorder. However, we still don't fully understand how the mechanical properties of individual tissue constituents, such as cell nuclei or myelin, determine tissue mechanics. Here we developed a model predicting local tissue mechanics, which induces non-affine deformations of the tissue components. Using the mouse hippocampus and cerebellum as model systems, we show that considering individual tissue components alone, as identified by immunohistochemistry, is not sufficient to reproduce the local mechanical properties of CNS tissue. Our results suggest that brain tissue shows a universal response to applied forces that depends not only on the amount and stiffness of the individual tissue constituents but also on the way how they assemble. Our model may unify current incongruences between the mechanics of soft biological tissues and the underlying constituents and facilitate the design of better biomedical materials and engineered tissues. To this end, we provide a freely-available platform to predict local tissue elasticity upon providing immunohistochemistry images and stiffness values for the constituents of the tissue.
The CUT&amp;RUN suspect list of problematic regions of the genome
Authors: Anna Nordin, Gianluca Zambanini, Pierfrancesco Pagella, Claudio Cantù
Journal: Genome biology (2023)

Cleavage Under Targets and Release Using Nuclease (CUT&RUN) is an increasingly popular technique to map genome-wide binding profiles of histone modifications, transcription factors, and co-factors. The ENCODE project and others have compiled blacklists for ChIP-seq which have been widely adopted: these lists contain regions of high and unstructured signal, regardless of cell type or protein target, indicating that these are false positives. While CUT&RUN obtains similar results to ChIP-seq, its biochemistry and subsequent data analyses are different. We found that this results in a CUT&RUN-specific set of undesired high-signal regions.We compile suspect lists based on CUT&RUN data for the human and mouse genomes, identifying regions consistently called as peaks in negative controls. Using published CUT&RUN data from our and other labs, we show that the CUT&RUN suspect regions can persist even when peak calling is performed with SEACR or MACS2 against a negative control and after ENCODE blacklist removal. Moreover, we experimentally validate the CUT&RUN suspect lists by performing reiterative negative control experiments in which no specific protein is targeted, showing that they capture more than 80% of the peaks identified.We propose that removing these problematic regions can substantially improve peak calling in CUT&RUN experiments, resulting in more reliable datasets.
PB2402: CLINICAL CHARACTERISTICSAND PROGNOSIS RISK FACTORS OF NON-HODGKIN’S LYMPHOMA INVOLVING THE HEART
Authors: Yue Chen, Peipei Xu
Journal: HemaSphere (2023)

Topic: 20. Lymphoma Biology & Translational Research Background: Non-Hodgkin’s lymphoma(NHL) involving the heart involving the heart has the characteristics of rarity, lack of characteristic clinical manifestations, difficulty in early diagnosis and poor overall prognosis. Aims: To summarize the clinical characteristics and risk factors of NHL involving the heart, and evaluate the impact of different treatment options on prognosis. Methods: Sixty-sixpatients with non-Hodgkin’s lymphoma involving the heart diagnosed in the Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School were included. Clinical and follow-updata were analyzed retrospectively. Results: B cell lymphoma accounted for 95.24% of NHL involving the heart. Sixty-six NHL patients with heart involvement, 5 received surgical treatment alone, 40 received chemotherapy alone and 21 received chemotherapy combined with radiotherapy/surgical treatment. Median OS was 9 months and median PFS was 7 months. The median follow-up time was 31 months. The median OS of patients receiving Rituximab or liposomal doxorubicin was significantly longer(P <0.05). The sex, IPI score, multisystem involvement, ECG abnormalities, LDH level, serumβ2-microglobulin level were relevant factors affecting prognosis(P<0.05). IPI score and arrhythmia were independent risk factors affecting PFS and OS(P<0.05). Summary/Conclusion: Chemo-regimen including rituximab or liposomal doxorubicin is the first-line therapy for patients with NHL involving the heart, but its overall prognosis is poor. Timely diagnosisis necessary to improve patients’ clinical outcome. Keywords: Lymphoma
PB2332: CLINICAL CHARACTERISTICS AND OUTCOMES OF HIV-ASSOCIATED AGGRESSIVE B-CELL NHL IN CHINA
Authors: Chaoyu Wang, Jun Liu, Yao Liu
Journal: HemaSphere (2023)

Topic: 19. Aggressive Non-Hodgkin lymphoma - Clinical Background: Little is known about the incidence, clinicopathologic characteristics, prognostic factors, and survival of lymphoma in people with HIV as these are less common than HIV-negative lymphoma, and currently, there are no standard guidelines for treatment of these patients. Aims: Therefore, we performed a study to analyze the clinical characteristics and outcomes of newly diagnosed HIV-associated aggressive B-cell non-Hodgkin’s lymphoma (NHL) patients in CUCH, as the largest HIV-associated lymphoma cohort in China so far. Methods: Totally 86 newly diagnosed HIV-associated aggressive B-cell NHL patients in CUCH, southwest China, from July 2008 to August 2021, were analyzed. Results: In the the entire cohort, median age was 48 years (range, 23–87 years), and more patients were male (87.2%). Most patients had elevated lactate dehydrogenase (LDH) (82.6%), advanced ann arbor stage (80.2%) and high IPI score (IPI score, 3-5) (62.7%) at diagnosis. Median CD4+ T cell count at diagnosis was 191/μl (range, 4-1022), 84 patients (97.7%) were on combination antiretroviral therapy (cART) at lymphoma diagnosis. With a median follow-up of 44.5 months (range, 2-160 months), median OS in the no received anti-lymphoma chemotherapy, only received one or two cycles and more than two cycles groups were 4 months, 9 months, and not reached, respectively (p=0.002). Cox multivariate analysis showed that age ≥60 (HR=3.162, 95%CI 1.500-6.665; p=0.002) and received less than two cycles of chemotherapy (HR=0.524, 95%CI 0.347-0.791; p=0.002) were independent risk factor for adverse prognosis based on OS. Summary/Conclusion: Overall, these data indicated that standardized anti-lymphoma therapy and rituximab administration were significantly associated with improved outcomes. Keywords: B cell lymphoma, HIV
Frontotemporal lobar degeneration
Authors: Murray Grossman, William W. Seeley, Adam L. Boxer, Argye E. Hillis, David S. Knopman, Peter A. Ljubenov, Bruce Miller, Olivier Piguet, Rosa Rademakers, Jennifer L. Whitwell, Henrik Zetterberg, John C. van Swieten
Journal: Nature Reviews Disease Primers (2023)
Policy-making and implementation for newborn bloodspot screening in Europe: a comparison between EURORDIS principles and UK practice
Authors: Silvia Lombardo, Farah Seedat, David Elliman, John Marshall
Journal: The Lancet Regional Health - Europe (2023)

Newborn bloodspot screening (NBS) policy is a contentious area in Europe. Variation in the screening panels on offer, in the approach to evidence assessment and in the use of health economic modelling are some of the issues which are debated on the topic. In this paper we focus on a set of patient-driven principles for newborn screening published by EURORDIS and use these as a reference point for exploration and comparison with NBS policy development and screening practice in the UK. In doing so, we share UK practice; we note the UK is generally well aligned with many of the recommended principles, but we also discuss areas of controversy and challenges. Some of these, like 'actionability', will undoubtedly continue to be debated and may never reach consensus. For others, such as patient and public voice participation in newborn screening systems, there are opportunities to continue improving existing processes and developing new mechanisms for stakeholder participation. Screening bodies in other European countries should also compare their policy-making and implementation practices with the EURORDIS principles to stimulate further discussion on the challenges and opportunities of newborn screening and provide a cross-European baseline.
Sex-specific risks for cardiovascular disease across the glycaemic spectrum: a population-based cohort study using the UK Biobank
Authors: Christopher T. Rentsch, Victoria Garfield, Rohini Mathur, Sophie V. Eastwood, Liam Smeeth, Nish Chaturvedi, Krishnan Bhaskaran
Journal: The Lancet Regional Health - Europe (2023)

We sought to examine sex-specific risks for incident cardiovascular disease (CVD) across the full glycaemic spectrum.Using data from UK Biobank, we categorised participants' glycated haemoglobin (HbA1c) at baseline as low-normal (<35 mmol/mol), normal (35-41 mmol/mol), pre-diabetes (42-47 mmol/mol), undiagnosed diabetes (≥48 mmol/mol), or diagnosed diabetes. Our outcomes were coronary artery disease (CAD), atrial fibrillation, deep vein thrombosis (DVT), pulmonary embolism (PE), stroke, heart failure, and a composite outcome of any CVD. Cox regression estimated sex-specific associations between HbA1c and each outcome, sequentially adjusting for socio-demographic, lifestyle, and clinical characteristics.Among 427,435 people, CVD rates were 16.9 and 9.1 events/1000 person-years for men and women, respectively. Both men and women with pre-diabetes, undiagnosed diabetes, and, more markedly, diagnosed diabetes were at higher risks of CVD than those with normal HbA1c, with relative increases more pronounced in women than men. Age-adjusted HRs for pre-diabetes and undiagnosed diabetes ranged from 1.30 to 1.47; HRs for diagnosed diabetes were 1.55 (1.49-1.61) in men and 2.00 (1.89-2.12) in women (p-interaction <0.0001). Excess risks attenuated and were more similar between men and women after adjusting for clinical and lifestyle factors particularly obesity and antihypertensive or statin use (fully adjusted HRs for diagnosed diabetes: 1.06 [1.02-1.11] and 1.17 [1.10-1.24], respectively).Excess risks in men and women were largely explained by modifiable factors, and could be ameliorated by attention to weight reduction strategies and greater use of antihypertensive and statin medications. Addressing these risk factors could reduce sex disparities in risk of CVD among people with and without diabetes.Diabetes UK (#15/0005250) and British Heart Foundation (SP/16/6/32726).